Submissions for variant NM_000046.5(ARSB):c.1178A>C (p.His393Pro)

gnomAD frequency: 0.00004  dbSNP: rs118203944

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000424623	SCV000517248	pathogenic	not provided	2015-05-27	criteria provided, single submitter	clinical testing	The H393P variant in the ARSB gene is a common MPS VI variant that has been reported in thehomozygous and the compound heterozygous state in multiple unrelated individuals withmucopolysaccharidosis type VI (MPS VI). Patients with the H393P variant who were compoundheterozygous for different missense variants were reported with variable disease severity (Litjens et al.,1996; Karageorgos et al., 2007). Functional studies of the H393P substitution indicate that it is a severe nullallele resulting in an undetectable enzyme level (Litjens et al., 1996). The H393P variant was notobserved with any significant frequency in approximately 6500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variantin these populations. The H393P variant is a non-conservative amino acid substitution, which occurs at aposition that is conserved across species. Missense variants in nearby residues (E390K and F399L) havebeen reported in the Human Gene Mutation Database in association with MPS VI (Stenson et al., 2014),supporting the functional importance of this region of the protein. We interpret H393P as a pathogenic variant.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000000934	SCV000802966	uncertain significance	Mucopolysaccharidosis type 6	2018-01-01	criteria provided, single submitter	curation	Very low frequency in ExAC (PM2); Reputable source identifies as pathogenic (PP5)
Invitae	RCV000000934	SCV001234817	pathogenic	Mucopolysaccharidosis type 6	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 393 of the ARSB protein (p.His393Pro). This variant is present in population databases (rs118203944, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 11939792, 17458871). ClinVar contains an entry for this variant (Variation ID: 886). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSB protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSB function (PMID: 8651289). This variant disrupts the p.His393 amino acid residue in ARSB. Other variant(s) that disrupt this residue have been observed in individuals with ARSB-related conditions (PMID: 26609033, 27826022), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000000934	SCV004208726	pathogenic	Mucopolysaccharidosis type 6	2023-10-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000424623	SCV004226557	pathogenic	not provided	2022-01-28	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3, PS3, PS4_moderate
OMIM	RCV000000934	SCV000021084	pathogenic	Mucopolysaccharidosis type 6	1996-06-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000000934	SCV001457624	pathogenic	Mucopolysaccharidosis type 6	2020-09-16	no assertion criteria provided	clinical testing